Several TNF antagonists, mainly monoclonal antibodies, have shown to be efficacious in the therapy of Crohn's disease. Despite the fact that they have been used for over a decade, their precise mechanism of action is still a matter of investigation. The effects of anti-TNF agents are mediated by multiple mechanisms including direct neutralization of soluble TNF and interaction with membrane-bound TNF. Anti-TNF agents may act by reduction of proinflammatory cytokine levels, elimination or clearance of active inflammatory cells from inflamed tissue which can conceptually be achieved by a number of mechanisms including apoptosis induction, antibody and complement mediated cytotoxicity and inhibition of cell migration into the intestinal tissue. Regulatory events both in the cellular and intracellular levels probably play a role as well. Finally, effects of anti-TNF agents may vary according to their physical contact with TNF leading to different binding avidities, conformational changes and variable downstream effects. These effects may also be influenced by structural differences in the non-TNF binding domain which affects the ability of each drug to interact with the immune system. Our understanding of these mechanisms of action is limited by the fact that much of the data was obtained using artificial in vitro systems of which their relevance to the in vivo situation is uncertain.